Calcium Signaling: From Normal B Cell Development to Tolerance Breakdown and Autoimmunity

Abstract

Maintenance of self-tolerance of auto-reactive lymphocytes is a fundamental mechanism to prevent the onset of autoimmune diseases. Deciphering the mechanisms involved in the deregulations leading to tolerance disruption and autoimmunity is still a major area of interest to identify new therapeutic targets and options. Ca²⁺ signaling plays a major role in B cell normal development and is therefore finely tuned by B cell receptor (BCR)-dependent and independent pathways. Developmental changes in the characteristics of BCR-dependent Ca²⁺ signals as well as the modulation of basal intracellular concentration ([Ca²⁺]_i) contribute strongly to self-tolerance maintaining mechanisms responsible for the physical or functional elimination of autoreactive B cells such as clonal deletion, receptor editing, and anergy. Implication of Ca²⁺ signals in B tolerance mechanisms mainly occurs through the specific activation of transcriptional programs depending on the amplitude, shape, and duration of Ca²⁺ signals. A large number of studies reported Ca²⁺ signaling defects in autoimmune pathology such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and primary Sjӧgren's syndrome (pSS). However, the precise nature of the molecular events responsible for these deregulations is not fully understood. Moreover, the demonstration of a direct correlation between Ca²⁺ signaling defects and tolerance disruption is still lacking. The recent identification of proteins involved in B cell Ca²⁺ signals such as ORAI, stromal interaction molecule and transient receptor potential is opening new horizons for understanding Ca²⁺ signaling defects observed in autoimmune diseases and for proposing potentially new therapeutic solutions. This review aims to present an overview of the developmental evolution of BCR dependent Ca²⁺ signaling and to place this signaling pathway in the context of mechanisms involved in tolerance maintenance and breakdown.

Keywords: Autoimmunity; B cells; Calcium pathway; Calcium signaling; ORAI; Primary Sjӧgren’s syndrome; STIM; Systemic lupus erythematosus; TRPC; Tolerance.